Oral Cancer News
Compiled by The Oral Cancer Foundation

Monthly Archives: March 2008

Introduction
The fact that mucositis remains an important toxicity of cancer therapy was reflected in the thirty abstracts dealing with this topic that were included in this year’s MASCC/ISOO symposium. While mucositis has most often been associated with damage to the oral cavity, it is clear that its clinical and scientific import to the rest of the gastrointestinal tract is significant. Abstracts presented fell into a range of topics that spanned preclinical mechanistic studies to interventional clinical trials. Among the major subject categories addressed were techniques and instruments to assess mucositis and observational reports of its behavior, incidence and risk, animal and human studies of the biological basis for mucositis, the burden of illness of mucositis, and clinical trials of specific interventions.

Mucositis Assessment, Incidence, Risk Factors, and Burden

A number of studies reported on the assessment of mucositis, its incidence, risk factors, and impact on quality of life, health, and economic outcomes.

Dudley, et al. reported the application of an innovative statistical approach to quantify parameters of change for patient populations, model individual variability about population parameters, and predict which patients would be most severely affected. Their approach, known as Latent Growth Curve Analysis (LGCA), was applied to estimate parameters of change in erythema in 133 HSCT patients treated with high-dose chemotherapy conditioning regimens. Clinical ratings of erythema from the 20 item Oral Mucositis Index were made 8 times over a 3-week period. The model identified statistically significant individual variability relative to the average slope and quadratic parameters. Additional analyses are planned in the future.[1]

As part of a psychometric analysis, Cheng, et al. administered a 41-item oropharyngeal mucositis quality-of-life scale (OMQoL) questionnaire to 210 patients with oropharyngeal mucositis. Ninety percent of the study population was being treated for solid tumors. Patients were well distributed for mucositis severity (WHO grades 0 to 3). The initial psychometric analysis resulted in four subscales depicting problems with symptoms, diet, social function, and swallowing, which was driven by 31 of the 41 items on the scale. The authors concluded that the 31-item OMQoL was a psychometrically sound measure of measuring the quality of life of patients with oral mucositis. In a second abstract, the same authors demonstrated that the OMQoL was effective in demonstrating that traditionally stomatotoxic chemotherapy or chemoradiation regimens were associated with a poorer quality of life, especially with respect to symptoms, swallowing, and diet. [2]

Dorr, et al. evaluated the potential impact of gender on the risk of radiation-induced oral mucositis in patients being treated for cancers of the head and neck. In a retrospective analysis of 362 patients of both genders (♀ = 80, 22%) treated in similar fashion, mucosal reactions in females occurred at the same rate as in men, but were diagnosed slightly later among patients receiving conventional fractionation. The authors attributed this observation to more intensive mouth care by women, and concluded that women do not require particular attention in addition to routine supportive care.[3]

Three retrospective studies described the incidence of oral mucositis in various patient populations. Of 39 patients being treated with a range of high-dose chemotherapy regimens, Eilers, et al. reported mucosal barrier breakdown in 38.5% using Oral Assessment Guide criteria. DeMoor, et al. examined symptoms of oral mucositis among 11,537 cancer patients being treated for common, non-head and neck solid tumors with multicycle therapy at six community oncology clinics.[4] Mucositis symptoms were determined using patient reponses on a 10 Likert scale (0 not a problem, 10 as bad as possible) recorded on an e-tablet computer at the time of patients’ office visits. The authors noted that average mouth sore scores peaked by day 40 (Cycle 2), and that patients who reported any symptoms of mouth sores by day 21 (Cycle 1) were five times more likely to develop severe mucositis by day 126 than patients who reported no symptoms. The authors concluded that mucositis is common in community oncology. Finally, in a retrospective chart review of 95 patients being treated for osteosarcoma, Carrillo, et al. noted 70 mucositis episodes (67%) across two treatment protocols.[5]

To assess risk for oral mucositis in children, Cheng, et al. evaluated 102 patients (51 patients with WHO grade ≥2 and 51 controls) in a matched case-control study. The mean age of study participants was 7.6 years and 65% were males. The authors found that decreasing neutrophils and body weight and increasing body height were significant risk factors for mucositis in the study population.[6]

As a means to better understand mechanism and risk for mucositis in patients with acute myelogenous leukemia (AML), Brennan’s group examined changes in gene expression in five patients being treated for AML as detected by microarray analysis of RNA obtained from biopsies of the buccal mucosa before and after chemotherapy. They found that 32 genes were differentially expressed, among them agininosuccinate synthase, an enzyme that has importance in the maintenance of protective levels of nitric oxide. RT-PCR was used to confirm the microarray results. The authors concluded that the down regulation of argininosuccinate synthase following chemotherapy in AML patients may constitute a risk for acquiring oral mucositis.

Grunberg, et al. reported the results of an interim analysis of the first 20 of a planned 150 colorectal cancer patients receiving FOLFOX chemotherapy in a multinational, 44 center investigation. Oral mucositis and diarrhea were identified from patient reports (oral mucositis daily questionnaire modified to add questions about diarrhea) which patients completed at baseline and daily during treatment. In addition, two validated QoL questionnaires were administered at baseline and then weekly during treatment. Sixty-five percent of patients reported mouth and throat soreness, and 35% reported severe MTS. Seventy percent reported diarrhea and 45% had severe diarrhea. The authors noted that MTS and diarrhea often occurred together. Patients with MTS had poorer quality of life outcomes as measured by both FACT-E and FACIT-Fatigue questionnaires.[7]

Dorr and his colleagues evaluated the relationship between patient self-evaluation of their mouths during radiochemotherapy and clinician derived mucositis scores derived in the same patients based on RTOG/EORTC criteria in 366 patients. During treatment, VAS-values significantly decreased. From the third treatment week, subjective VAS values were significantly lower in those patients who were scored with confluent oral mucositis. The authors concluded that RTOG/EORTC clearly mirrors the subjective assessment of patients, and that the agreement indicates that mucositis significantly impacts on patients’ quality of life.[8]

Nicolatou-Galitis, et al. reported the incidence and severity of mucositis among 93 patients receiving radiation therapy for cancers of the head and neck. Of the 93 patients studied, 80 completed treatment as planned; 13 required treatment interruptions. Using EORTC/RTOG criteria, severe mucositis was noted in 57% of patients. Interestingly, 25 (of 53) showed improvement in mucositis score with the administration of an anti-infectious agent (antiviral or antifungal).[9]

In addition to its high incidence, Keefe, et al. reported that oral mucositis is associated with increased resource use among patients receiving treatment for cancers of the head and neck. Sixty-nine patients with cancers of the mouth, oropharynx, hypopharynx, or larynx whose planned treatment included conventional, intensity modulated radiation therapy with or without chemotherapy were enrolled at the start of therapy in a multinational, multiinstitutional study.[10] Mucositis severity was assessed using a validated symptom questionnaire for oral mucositis. Ninety percent of patient reported moderate to severe mucositis. Of these, the majority were being treated for cancers of the mouth or oropharynx. Patients with mouth cancers had slightly more mucositis symptoms than did patients with tumors of the larynx or hypopharynx. Severe mucositis symptoms were reported in 92% of patients with mouth cancers and 82% of patients with larynx/hypopharynx cancers. Resource use exceeded that previously reported. Among patients with moderate to severe mucositis, gastrostomy tubes were required in 25%, unplanned office visits in 37%, hospitalization in 18%, and transfusion in 5%. Even low grade mucositis was associated with unexpectedly high resource utilization.

The Biology of Mucositis

No longer is mucositis viewed as being biologically simple. Rather, it is now recognized that the pathobiology underlying the genesis of regimen-related mucosal injury is complex. A number of abstracts provided data that support that hypothesis and offered evidence of the roles of p53, NF-κB, and inflammatory cytokines in mucositis development.

Yeoh, et al. used a novel animal model in which fractionated radiation was administered to Dark Agouti rats to study the expression of p53, NF-κB, and COX-1 and -2 during the development of mucositis.[11] The authors compared jejunal and colonic samples obtained weekly from animals that had received 2.5Gy of radiation thrice weekly for up to six weeks with unirradiated controls. The TUNEL assay was used to determine apoptosis, and immunohistochemistry was performed to evaluate the expression of p53, NF-κB, and cyclooxygenases. Mucosal injury was noted after only 1 week of RT. P53 was increased in both the jejunum and colon, and this corresponded to levels of apoptosis. NF-κB and COX-2 were also increased in the irradiated tissue. These results confirm the similarity of molecular pathways involved in mucositis throughout the gastrointestinal tract and the early increase in COX-1 suggests its possible role in the pathogenesis of the condition.

In rodent model of irinotecan-induced mucosal injury, Logan and his colleagues evaluated tissue levels of NF-κB, TNF, and interleukins-1b and -6 using standard immunohistochemical techniques. Following the administration of irinotecan, rats were sacrificed from 30 minutes to 72 hours and buccal mucosa, jejunum, and colon were collected and studied. Altered histological features were noted in all of the tissues studied by 72 hours. Subtle changes were also noted in the intestinal sample as soon as 6 hours after chemotherapy injection. Tissue levels of NF-κB, TNF, IL-1b, and IL-6 peaked between 2 and 6 hours in the tissues examined. The authors concluded that their results provide additional evidence to the pivotal role of NF-κB and associated cytokines in the pathogenesis of mucositis.[12]

Xanthinaki and her group evaluated apoptotis and markers of inflammation in head and neck cancer patients with varying levels of radiation- (with or without chemotherapy) induced oral mucositis. Cytologic smears were obtained by brush biopsy from the oral cavities of 35 patients, and the relationship between selected apoptotic and inflammatory markers and the clinical severity of oral mucositis (as measured by EORTC/RTOG criteria) was studied.[13] Whereas the proapoptotic marker, p53, was seen in 6.5% of patients with no mucositis and 43% of patients with severe mucositis (grade 3), antiapoptotic markers (bcl-2 and mcl-1) were highly expressed in patients with no mucositis and less expressed in patients with severe injury. TNF and IL-1β expression were more frequent in patients with clinically significant mucositis than in patients without the condition.

Interventional Studies for the Prevention or Treatment of Mucositis

A number of agents were tested in preclinical and clinical studies. Among these were growth factors, vitamin therapy, a mitogen, cryotherapy, and laser therapy.

The efficacy of palifermin on 5-FU-induced intestinal injury was studied in a rodent model by Butler, et al. Seventy-two hours following three daily subcutaneous injections of palifermin at doses of 5, 10, or 15 mg/kg into groups of 10 Dark Agouti rats, the animals received a single injection of 5-FU (50 mg/kg). Using the 13C sucrose breath test as a marker to evaluate the health of the small intestine, the authors reported that palifermin administration at dose of 15 mg/kg/day resulted in a significant protective effect against 5-FU-induced intestinal injury.[14]

In another study in the same species, Chan, et al. investigated the mechanism by which palifermin exerts its protective effect on irinotecan-induced mucositis. Groups of 6 Dark Agouti rats received palifermin only, saline, irintecan only, or irinotecan plus palifermin. Rats were sacrificed at various times following chemotherapy and jejunal, and colonic expression of KGF and KGF-receptors were studied using immunohistochemical techniques.[15] Goblet cell characteristics were studied using Alcian Blue-Periodic Acid Schiff stain. The expression of KGF and its receptor was not noticeably different among study groups. The goblet cell population was significantly increased in the jejunum of rats that received palifermin, and goblet cells were maintained after chemotherapy in animals that had received palifermin compared with control animals. The authors concluded that palifermin exerts an anti-mucotoxic effect along the gastrointestinal tract by maintaining the number of goblet cells following chemotherapy administration.

Dexpanthenol (provitamin B5) was studied for its ability to modify radiation-induced oral mucositis in 366 patients being treated for cancers of the head and neck. The study, reported by Doerr, et al., compared the efficacy of mouth washes containing dexpanthenol or tap water, with or without additional mechanical debridement, on daily mucositis grades as measured by RTOG/EORTC criteria. The results of the study failed to demonstrate any advantage to dexpanthenol in the reduction of mucositis severity. [16]

ATL-104 is a recombinant protein of the L-form of phytohemagglutin, a plant lectin that is highly mitogenic for epithelial cells of the GI tract and resistant to acid and protease degradation. The results of a clinical trial were reported by Hunter, et al. in which ATL-104 was tested for its ability to affect oral mucositis in 104 patients receiving stomatotoxic conditioning regimens (high-dose melphalan or BEAM) prior to autologous HSCT. Subjects were randomized to receive one of three doses of ATL-104 (50 mg, 100 mg, 150 mg) or placebo as a 15 mL swish and swallow for three days before and three days after chemotherapy. Mucositis was assessed using WHO and WCCNR criteria for 28 days following dosing or until discharge. ATL-104 administration favorably affected the duration of mucositis compared to placebo, although no advantage was seen with increased concentrations of the test material (median duration of WHO grade 3-4 mucositis with placebo was 10.5 days, ATL 50 mg 2.0 days, ATL 100 mg 2.0 days, ATL 150 mg 3.0 days). No clear effect of ATL-104 on the incidence of severe mucositis was noted. ATL-104 was well-tolerated at all the doses studied. The authors concluded that further investigation of ATL-104 is warranted.[17]

A group from Dalarna and Uppsala Universities reported on the effects of oral cryotherapy on oral symptoms in patients receiving conditioning regimens prior to bone marrow transplantation. Ohrn, et al. compared the responses of a randomized group of 78 patients (half received cryotherapy and the others standard oral care) based on the completion of visual analog scales for 10 conditions of the mouth including pain, dryness, salivary viscosity, ability to talk, dysphagia, taste alterations, condition of the lips and gingival, and ability to perform oral hygiene.[18] The authors found a pattern suggesting that patients who received oral cryotherapy experienced fewer oral symptoms (not statistically significant).

The results of two randomized trials in which low level laser therapy was studied were presented. In a Phase III randomized, double blind, placebo controlled trial, Schubert and his colleagues compared the ability of two different low level GaA1As diode lasers (40 mW 100 nm and 60 nW 780 nm) to prevent oral mucositis in hematopoietic stem cell transplant patients who received stomatotoxic conditioning regimens. Seventy patients were randomized into one of three treatment groups (2 laser therapy, 1 placebo). Patients in the laser groups were treated throughout the mouth beginning on the first day of conditioning and continuing until two days after transplant. The severity of mucositis and oral pain was assessed twice weekly until three weeks after transplant using the Oral Mucositis Index and a VAS pain scale. The authors reported that both lasers were efficacious in reducing mucositis—the 100 nm wavelength being superior—and concluded that additional studies are warranted.[19]

In a different approach, Genot, et al. evaluated the ability of low energy laser treatment to delay the progression of mild mucositis to more severe grades. Thirty-six patients with hematological malignancies who had EORTC mucositis grades of 1 or 2 induced by stomatotoxic chemotherapy with or without radiation prior to HSCT were randomized to receive either treatment with low energy lasers (3J/cm2 ) or sham laser (n=18 per group). The frequency of laser treatment was not specified in the abstract. All patients had mild mucositis at study entry. The authors reported that while only three patients were treated with laser, 16 patients in the sham treated group went on to develop severe mucositis (grade 3). The time of progression of lesions to severe mucositis appeared to be delayed in the laser treated patients. The authors concluded that low level laser therapy appeared to be effective for the treatment of oral mucositis.[20]

Conclusions

Mucosal injury of the gastrointestinal tract is an important and largely unmet side effect of cytotoxic cancer therapy that has broad health and economic ramifications for cancer patients. Interest in the complex biology underlying this condition continues to result in studies that ultimately will define its pathogenesis and provide targets for treatment. Identification of risk factors will permit interventions to be appropriately targeted. The development of effective therapies for the prevention and treatment of mucositis remains a high priority and continues to be aggressively pursued.

The FDA is deciding whether to give young boys a vaccine that prevents cervical cancer in older women. Right now, Gardasil, which was developed at the U of R Medical Center, is given to girls ages 9 through 26.

Gardisil is the only vaccine available to protect against HPV, the virus that can cause cervical cancer. It was developed by the researches and the U of R Medical Center, and was marketed to teens beginning last year. But now the drug maker says giving it boys may help men from spreading the HPV virus.

A recent study in the New England Journal of Medicine finds that infection with HPV through oral sex is now the leading cause of throat cancer which strikes 11,000 men and women each year. HPV is also a major cause of anal cancer and genital warts both affect men and women.

Doctors say the increase in throat cancer is troubling because it’s usually associated with alcohol and heavy smoking. But we asked Dr. Michael Haben, a head and neck cancer expert with the Wilmot Cancer Center, and he said he’s not convinced there is enough evidence yet to support the vaccine for boys.

“I don’t think the research will bear out that we have a proven benefit from wither the transmission or a reduction in throat cancers related to any possible connection to the virus. I wouldn’t be the first to run out and have the HPV vaccine for boys,” said Otolaryngologist Haben.

Sometime this year Merck the maker of the vaccine will submit data to the FDA looking for approval to give Gardasil to boys.

In Australia, Mexico and some European countries the vaccine is approved for boys.

Well, these “breakthrough” treatments are here, according to a recent American Cancer Society report that said as many as 50 percent of cancer deaths could be prevented with lifestyle changes, such as quitting smoking, maintaining a healthy weight, and getting screened for certain malignancies.

“Nearly half of all cancer is related to two things — tobacco and obesity,” said Dr. Jay Brooks, chief of hematology/oncology at Ochsner Health System in Baton Rouge, La. “That’s something I don’t think people truly grasp.”

Dr. Neil Hayes, a medical oncologist specializing in lung and head and neck cancers at the University of North Carolina School of Medicine, concurred. “Most of my patients are smokers, so it’s rare I see someone truly surprised by the diagnosis. But I don’t think they fully think through the risk associated with smoking,” he said.

Evaluating your risk of cancer, and taking steps to modify those risk factors within your control, could save your life.

Smoking is far and away the leading cause of preventable cancer deaths. In the United States, nearly one-third of all cancer deaths — more than 170,000 Americans — each year are related to tobacco use, according to the American Cancer Society (ACS). Yet, almost one in four American adults still uses tobacco. And, about 22 percent of teens are still lighting up.

“Not smoking is the single most important thing you can do to lower your risk of cancer,” Brooks said.

Another important risk factor cited by the cancer society is the increasing girth of the average American. Poor nutrition, lack of exercise, and excess weight are likely at the root of as many as 188,277 cancer deaths annually, according to the ACS.

A recentNew England Journal of Medicinestudy that included more than 900,000 U.S. adults found that the heaviest people had the highest risk of death — 52 percent higher for men and 62 percent for women — compared to people of normal weight.

However, what isn’t yet known, Hayes said, is if proper nutrition can prevent that increased risk. “We have an incomplete understanding of diet’s impact on cancer. But a healthy lifestyle is associated with all kinds of good things,” he said.

The ACS recommends eating at least five servings of fruits and vegetables a day, and getting at least 30 to 60 minutes of moderate to vigorous activity at least five days a week. Walking, biking and skating are examples of moderate activity, while jogging, fast bicycling, weight training, aerobics and swimming are considered vigorous activity.

Hayes said too much alcohol is also associated with some cancers, particularly tumors of the esophagus, pharynx, and mouth. The ACS recommends that women drink no more than one alcoholic beverage a day and men no more than two alcoholic drinks a day.

Then there’s the lifesaving issue of screenings. Some cancer screenings, such as those for skin, breast, cervical and colon cancers, can actually detect precancerous changes that may eventually lead to malignancies.

For instance, with a colonoscopy a doctor can find and remove polyps before they turn into cancer. The ACS report estimated that as many as half of the 55,000 colon cancer deaths that occur each year could be prevented with proper screening.

“Aside from avoiding tobacco and maintaining a healthy body weight, cancer screening is the most important thing people can do to reduce their chances of dying from cancer,” the ACS report stated.

To learn more about cancer prevention, visit the Cancer Research and Prevention Foundation.

Persons with a certain type of homozygosity (having two identical copies of the same gene, one inherited from each parent), may have a greater predisposition to cancer, according to a new study.

In previous research, the authors observed a low frequency of germline (those cells of an individual that have genetic material that could be passed to offspring) heterozygosity (possessing two different forms of a particular gene, one inherited from each parent) in cancer patients compared with controls, raising the question whether homozygosity could play a role in cancer predisposition.

“Homozygosity is common in humans and extended homozygote tracts have been described in several studies. Cancer susceptibility genes are also numerous in the genome. These facts together increase the likelihood that homozygosity might occur in the loci [the specific site of a particular gene on its chromosome] of cancer susceptibility genes. One can then hypothesize that germline homozygosity at these loci may somehow contribute to cancer predisposition,” the researchers write.

Charis Eng, M.D., Ph.D., of the Cleveland Clinic Foundation, and colleagues conducted a study to determine the frequency of germline homozygosity in a large series of patients with three different types of solid tumors compared with population-based controls. The study included germline and corresponding tumor DNA, which was isolated from 385 patients with carcinomas (147 breast, 116 prostate, and 122 head and neck carcinomas), and was subjected to genetic analysis.

The researchers found: “Our data derived from 3 different solid tumors, validated in a fourth, demonstrate that high frequencies of germline homozygosity at specific markers are associated with these cancers compared with controls … Importantly, we were able to independently validate our observations in a different type of solid tumor, lung carcinoma, by showing an increased frequency of germline homozygosity in cancer cases compared with ancestry-matched controls.”

“… our observations here should be validated in these solid tumors and explored in other malignancies. If our data can be robustly replicated independently, then germline homozygosity at specific loci as low-penetrance alleles [one of a number of alternative forms of the same gene occupying a given position on a chromosome] predisposing to carcinomas could be taken into account in future cancer risk assessments and management beyond high-penetrance cancer susceptibility genes. Additionally, with further studies and fine structure analyses, it may be possible to use such data to predict the likelihood of loss of heterozygosity in a tumor at specific genomic loci if we knew the relative frequencies of germline homozygosity/heterozygosity at those same loci,” the authors write.

One day soon patients may spit in a cup, instead of bracing for a needle prick, when being tested for cancer, heart disease or diabetes. A major step in that direction is the cataloguing of the “complete” salivary proteome, a set of proteins in human ductal saliva, identified by a consortium of three research teams, according to an article published today in the Journal of Proteome Research. Replacing blood draws with saliva tests promises to make disease diagnosis, as well as the tracking of treatment efficacy, less invasive and costly.

Saliva proteomics and diagnostics is part of a nationwide effort to create the first map of every human protein and every protein interaction, as they contribute to health and disease and as they act as markers for disease states. Following instructions encoded by genes, protein “machines” make up the body’s organs and regulate its cellular processes. Defining exact protein pathways on a comprehensive scale enables the development of early diagnostic testing and precise drug design. In the current study, researchers sought to determine the “complete” set of proteins secreted by the major salivary glands (parotid, submandibular (SM) and sublingual (SL)). Recent, parallel efforts that mapped the blood (plasma) and tear proteomes allows for useful comparisons of how proteins and potential disease markers are common or unique to different body fluids.

“Past studies established that salivary proteins heal the mouth, amplify the voice, develop the taste buds and kill bacteria and viruses,” said James E. Melvin, D.D.S., Ph.D., director of the Center for Oral Biology at the University of Rochester Medical Center, and an author on the paper. “Our work, and the work of our partners, has shown that salivary proteins may represent new tools for tracking disease throughout the body—tools that are potentially easier to monitor in saliva than in blood,” said Melvin, who conducts his research at the Eastman Dental Center, in collaboration with the research labs of Mark Sullivan, Ph.D., and Fred K. Hagen, Ph.D.

The National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, funded the current study. The saliva proteome study represents a consortium effort with research teams at The Scripps Research Institute (John R. Yates III), University of Rochester, University of Southern California (Paul Denny), The University of California at San Francisco (Susan J. Fisher) and UC Los Angeles (David T. Wong, Joseph A. Loo).

Not Your Parent’s Saliva

To describe the results of the current study, it is important to note that the definition of saliva is evolving. Saliva once referred to everything in oral fluid, including: bacterial waste products, dead cells that had shed from mucous membranes and substances oozing from gum crevices. Among researchers today, however, the term saliva is increasingly reserved for just the salivary gland secretions (ductal saliva). The new definition is significant because of the emerging theory that the mix of proteins in ductal saliva tracks closely with that of blood, making saliva a potential diagnostic stand-in for blood.

To construct a credible protein list for saliva, the teams used competing techniques both to capture the greatest number of protein candidates for the list and to lend extra credibility to those found using different methodologies. Each team subjected saliva collected from patients to some form of mass spectrometry, which determines the identity of proteins based on measurements of their mass and charge. Saliva was collected from 23 adults of several races and both sexes. Although small, the set of study subjects was large enough to serve as a baseline list for near-future comparisons between healthy people and individuals with major diseases, researchers said.

Using mass spectrometry techniques, three teams at five institutions identified 1,166 proteins in parotid and submandibular/sublingual saliva. The results indicated that more than a third of saliva proteins were found in the blood proteome, as well. Comparison of these proteins against known protein pathways and other proteomes provided a first glimpse of the function of the core proteins. In addition, a number of the salivary proteins were found to match proteins with known roles in Alzheimer’s, Huntington’s and Parkinson’s diseases; breast, colorectal and pancreatic cancer; and type I and II diabetes. Specifically, a majority of the proteins were found to be part of signaling pathways, which is central to the body’s response to (and thus diagnosic of) system-wide diseases, researchers said.

Determining the salivary proteome is only the first step toward salivary-based diagnosis and treatment. These findings provide crucial protein information that is already being incorporated into microarray technology, a high-speed test that can determine the levels of multiple proteins, during disease progression. Related work is underway under within the NIH-funded Bioengineering Nanotechnology Initiative to design biochips, nano-scale computer chips packed with salivary protein chains. Protein probes on the chip react with proteins in a saliva sample, say from the mouth of someone with oral cancer, and inform a computer about which proteins are present.

“We believe these projects will dramatically accelerate diagnosis and improve prognosis by treating diseases at the earliest stages,” said Mireya González Begné, D.D.S., Ph.D., research assistant professor of Dentistry in the Center for Oral Biology at the Medical Center. “Researchers have already shown that saliva proteins can be used to detect oral cancer and HIV infection. We think this list will soon expand to include leading causes of death like cancer and heart disease, which, if caught early, are much more likely to be successfully treated.”

As part of an on going drug and alcohol awareness program, students were educated on the less-than-finer points of tobacco.

Kristen Ours, who works as a nurse at both Daw Middle School and East Liverpool City Hospital, gave a presentation on smoking and smokeless tobacco to Daw students Thursday. To demonstrate the harmful effects of smoking, a “smoking doll” was used to help students visualize what happens to a human’s lungs while smoking.

The doll would “puff” on a lit cigarette, causing the smoke and tar to stain the plastic receptor tube under the doll’s head. Ours and Wellsville D.A.R.E. officer Marsha Eisenhart, also passed around photos of healthy lungs, lungs afflicted from cigarette smoke, and lungs suffering from emphysema.

In addition to the harmful effects, Ours discussed reasons why children start smoking, citing peer pressure and a desire to look “grown up.” She also encouraged the students to talk to their parents about smoking, especially if the parents themselves smoke.

“You can’t order your parents to stop smoking, but you can encourage them to quit,” Ours said. “If they choose to quit, be their biggest supporter.”

Along with the doll, Ours showed students a sealed jar of tar from cigarettes. The thick, black substance was the amount of tar a person could intake from one year of smoking 20 cigarettes a day, Ours said.

Smokeless tobacco was also discussed, because Eisenhart said snuff and dip tobacco is becoming more and more popular.

“Snuff is on the rise, and it’s important for the students to see what it can do to people,” Eisenhart said.

Photos of two throat cancer victims were passed around so the students could see the results of chew tobacco and throat cancer. One of the photos was of 19-year-old Sean Marsee, who died from spreading cancer after his tongue and jaw were removed.

Ours used a model of a mouth afflicted with various types of cancer, growths and stains to show what can happen to someone who uses chew tobacco. The visual aides were from ELCH’s educational program.

After the presentation, Eisenhart challenged the students with questions who answered without hesitation. From their studies, students were able to recite facts such as more than 200 poisons in tobacco including nicotine, tobacco use leads to susceptibility to colds and upper respiratory problems and 400,000 people die each year from tobacco. She also discussed laws surrounding tobacco, such as legal age to purchase and where smoking is prohibited.

Eisenhart said the D.A.R.E. program was made possible from donations from local businesses. Donated money is used to purchase prizes up for drawing for each student who brings their completed D.A.R.E. workbook to class for each presentation.

The program educates students on topics ranging from tobacco to drugs, alcohol to bullying, and how to make good decisions.

Persons with periodontitis who also are infected with human papillomavirus (HPV) are at increased risk of developing tongue cancer, new research conducted at the University at Buffalo School of Dental Medicine has shown.

Periodontitis is a chronic inflammatory disease that destroys connective tissue and bone supporting the teeth. It has been associated with various systemic diseases, including diabetes and heart disease.

Researchers from UB and Roswell Park Cancer Institute published the first study showing an association between long-standing periodontitis and risk of tongue cancer in the May 2007 issue of Archives of Otolaryngology – Head and Neck Surgery. Studies conducted elsewhere have found that HPV is an independent risk factor for a subset of head and neck cancers.

The UB researchers now have shown that the two infections appear to work in tandem to boost the chances of developing tongue cancer.

Mine Tezal, D.D.S., Ph.D., assistant professor in the Department of Oral Diagnostic Sciences, UB dental school, and research scientist at Roswell Park Cancer Institute, presented results of this research today (April 4, 2008) at the 2008 American Association of Dental research meeting in Dallas, Texas.

Evidence of periodontitis-HPV synergy has important practical implications,” said Tezal, “because there is a safe treatment for periodontitis, but no treatment for HPV infection. If these results are confirmed by other studies, this has a tremendous relevance in
predicting and intervening in the initiation and prognosis of HPV-related diseases, including head and neck cancers.”

The study involved 30 patients newly diagnosed with squamous cell carcinoma on the base of the tongue between 1999 and 2005 at Roswell Park Cancer Institute for whom data was available on both periodontitis and tumor HPV status. Cumulative history of periodontitis was determined by assessing the loss of alveolar bone, the bones that underlie and support the teeth, via X-ray.

Tumor status was identified from paraffin-embedded tumor samples analyzed by polymerase chain reaction. Analysis concentrated on the presence of tumors containing the DNA of two of the most common types of HPV virus associated with oropharyngeal cancers, HPV-16 and HPV- 18.

Results showed that 63 percent, or 19 out of 30 patients, had tumors that were positive for HPV-16 DNA; none of the tumor samples were found to contain HPV-18 DNA. In addition, 90 percent of patients with tumors positive for HPV had periodontitis, and 79 percent of patients whose tumors showed no presence of HPV did not have periodontitis.

“HPV infection is a necessary, but not sufficient, cause of head and neck cancer,” said Tezal. “Although the majority of the population is infected with HPV at least once in their lives, most infections are cleared rapidly by the immune system and do not result in pathology.

“Persistence of HPV infection is the strongest risk factor for carcinogenesis,” she said. “Thus, the identification of factors that influence the persistence of HPV infection is critical to facilitate efforts to prevent head and neck cancers. This study implicates that chronic inflammation and co-infection with oral bacteria may be significant factors in the natural history of HPV infection.”

The study was supported by a grant to Tezal from the National Cancer Institute of NIH.

Cancer of the esophagus is one of the fastest growing cancers in the United States. That’s why researchers in Seattle are hoping new technology in the form of a tethered endoscope will make screening for throat cancer cheaper and faster, and more likely to be covered by all insurance companies.

Biomedical engineer Eric Seibel is about to swallow a small camera the size of pill. Each swallow of water is pushing a one-pixel camera lower into his esophagus. A tether controls where it goes as it takes 30 color pictures per second on its way to his stomach.
He said, “We have a little scanner and we scan very low-powered laser light to get the high resolution imaging.”

Researchers believe this new endoscope will be cheaper to use and more effective at screening the digestive tract for pre-cancerous conditions like Barrett’s esophagus –or- throat cancer.

Doctor Seibel said, “To look for something right above your stomach at the bottom of your esophagus, that’s where you get heart burn and that’s where a lot of the esophageal cancers start. And what you would like to have is a little tether and a camera to look right at that point, make that diagnosis, confirm that diagnosis and then just pull it out.”

Normal endoscopes require patients to be sedated. This new technology is faster and cheaper because patients are awake.

Karen Murray, a gastroenterologist said, “If someone is having a lot of heartburn pain and you wanted to see if there was significant, visible esophogitis, you could do that quite easily. And if there was a concern, but not obvious proof that there was a foreign body in the esophagus, one could take a look and pull this back out.”

Future uses for the tethered endoscope could include more than pictures. Researchers believe some day they might be able to deliver treatments through the device.

This isn’t the first pill-sized endoscope. Wireless capsules have been around for a few years… but they’re designed to pass through the body and only allow a single fly-by view. Patients who swallow the tethered endoscope would give doctors the ability to see all areas of concern. Researchers hope to begin clinical trials on their new device soon.

Researchers from the Dental Institute and the Nutritional Science Research Division, led by Professors Saman Warnakulasuriya and Victor R Preedy have published new research findings which herald a significant advance in understanding how alcohol may cause oral (mouth) cancer.

Oral cancer affects around 4,600 people in the UK per year and the disease is more common in Scotland. It is a highly lethal disease and five year survival is around 50 per cent. At least three people die of or with oral cancer every day in the UK.

Saman Warnakulasuriya, Professor of Oral Medicine & Experimental Pathology at King’s, and lead researcher in the project says: ‘We are very excited by this discovery. Alcohol is a major risk factor for oral cancer. We have so far not been able to explain exact mechanisms how alcohol causes cancer of the mouth’.

Through study of a group of alcohol misusers the researchers have found that a break down product of alcohol – acetaldehyde can be detected in oral mucosal cells, and thereby provide a marker for alcohol metabolism.

The research team at King’s worked in collaboration with Professor Onni Niemela and Professor Seppo Parkkila at the University of Tampere, Finland. Dr Onni Niemela, a Professor of Laboratory Medicine at the University of Tampere, comments: ‘This product (acetaldehyde) identifies cells that are damaged by the alcohol, and through the study of these cells we can see how the damage may trigger diseases such as cancer in alcohol misusers’.

During alcohol ingestion acetaldehyde appears to react with proteins in the mouth to form rigid bonds with amino acids, otherwise known as adducts. This reaction interferes with both protein structure and function irreversibly. As a result the immune system recognises these adducts/bonds as foreign and fires off an inflammatory response.

In such cases, Acetaldehyde may also bind to DNA and blocks DNA repair machinery thereby triggering mutations and instigating cancers. A further combination of both tobacco and alcohol increase the dangers of acetaldehyde, and thereby the risk of cancer. ‘These new findings have illuminated a potential screening tool to detect who may have alcohol induced damage in their oral mucosal cells.

Acetaldehyde Discovery

Victor R Preedy, Professor of Nutritional Biochemistry at King’s who contributed to this research, says: ‘The discovery of acetaldehyde adducts in tissues is very important and helps us understand how diseases may be caused. In this case the information adds to our understanding of mouth cancer. Acetaldehyde is a very small molecule and occurs naturally but in some circumstances it can be very damaging. We need to know much more about acetaldehyde’.

Dr Toru Nagao, Chief Maxillofacial Surgeon at Okazaki City Hospital in Japan who contributed tissue samples from a Japanese population for comparison with British subjects was keen to highlight the significance of the study to Japanese researchers and says: ‘There are genetic differences in Japanese populations that affect metabolism of alcohol, and few who cannot further breakdown acetaldehyde due to missing enzymatic mechanisms. Finding acetaldehyde in oral tissues may in the future be a marker for such aberrative pathways of alcohol metabolism’.